Bisphosphonates (BPs) halt bone loss and prevent osteoporosis-related fractures in the more than 4 million Americans currently using these drugs, but long-term BP use may be linked to clinically relevant loss of load-bearing mechanical strength. This remains a significant unanswered challenge to the medical community. The broad long-term objective of the proposed study is to provide new information regarding the time- dependent effects of BP on bone stiffness and strength and thus to improve the confidence of physicians and patients regarding use of BPs for treating the world's more than 200 million osteoporotic patients. The goal of this study is to use an advanced conceptual approach and data obtained from the parent study, to quantify bones load-bearing mechanical competence as a function of long-term BP treatment. The proposal tests the central hypothesis that long-term BP treatment is characterized by time- dependent favorable and unfavorable changes in bone quality. The specific aims are to: 1) build a new interdisciplinary research team that contributes needed expertise in finite element (FEA) and advanced regression analyses 2) use micro-CT imaging to construct 3D models of bone, incorporate parent-study derived structure and material data into these models, evaluate these models by using FEA, calculate functionally relevant bone stiffness and strength parameters, and 3) analyze the BP treatment time-dependent changes in these parameters using advanced regression methods. These aims will be accomplished by adding new interdisciplinary investigators to the team to provide the needed technical expertise. Research methods to be used in this blinded cross-sectional study of 60 human bone samples identified in the parent study include micro-CT imaging and finite element analyses. Advanced nonlinear regression analyses will be used to evaluate the relationships between BP treatment duration and bone stiffness and strength. The results of the proposed study are expected to indicate when the maximum benefit of BP treatment is attained, the duration of this benefit, the time at which this benefit begins to decline, and the time at whih this benefit might return to baseline or dip below. These findings should remove the prevailing uncertainty regarding the safety of BP treatment and thereby providing major health and economic benefits. The anticipated findings of the proposed study are of great relevance to the NIAMS mission. They will change the current therapeutic paradigm for osteoporosis treatment and provide increased confidence to physicians and patients regarding BP use. Sustained benefits will accrue due to the efforts of the newly created interdisciplinary team and their continuing application of their collective expertise to address other metabolic bone diseases.